Getting Better is a short documentary that explores three remarkable

stories of medical progress: Cancer, HIV/AIDS, Surgery. The film looks

at the role of researchers and clinicians, of patients, their families and
their advocates, and how information is translated into action. It is the
story of research, clinical practice and patient care, and how we have
continued to get better over the last 200 years.
In 2012 the New England Journal of Medicine celebrates 200 years of
publishing practice - changing medical advances. NEJM brings together
a global community, from researchers to clinicians, to improve the
health of people around the world. The 200th anniversary of NEJM
honors all who contribute to this mission.

In 1812, the year the New England Journal of Medicine and Surgery first
started to publish, medical knowledge in the US and around the world
was limited. We had no understanding of infectious diseases. Health
outcomes were particularly poor for women and children. The surgery
was unsanitary and performed without anesthesia. Cancer was largely
unrecognized because so few people lived long enough to develop it.
Two centuries later, people in the US live longer and better than ever
before imagined. This film explores three remarkable stories of medical
progress. It looks at researchers and clinicians, patients and their
advocates, and how information is translated into action. Progress has
been uneven, but the advances have shown us that we can get better.

From rough to refined: The Rise of Surgery

Atul Gawande, MD, MPH: I'm a general and an endocrine surgeon I take
emergency calls, but much of my practice is in a very specialized area,
which is tumors of the endocrine glands. Eileen is a 50 year old graphic
designer who was found to have a nodule in her thyroid.
Eileen: I found the lymph myself, and I was like, I don't remember this
being here before.
Eileen's primary care physician sent her to see Dr. Gawande, who
performed an open biopsy on her thyroid a month earlier.
Gawande: It came back positive, and in fact, it had spread out of the
thyroid into the lymph nodes as metastatic disease. So we need to
remove the entire thyroid and lymph nodes.
Dr. Suzanne Klein is Eileen's anesthesiologist for her surgery today
We used to say, Don't worry about the surgery; it's the anesthesia. We
can't say that anymore.
The field of anesthesiology is continuously changing; new products and
research come out all the time.
In the last 25 years in particular, we went from one in 5,000 patients
dying from their anesthetic itself to less than 1 in 200,000, as rare as a
plane crash.
Before the introduction of ether anesthesia, surgery was just brutal and
terrifying. The patient would already be inebriated with alcohol and
other kinds of substances. It was incredibly bloody and gruesome. It
was typically an intervention of last resort.
Danny Jacobs, MD, MPH: I don't think I would have been a very good
surgeon if I had to hold someone down in order to do an operation.

In 1846, Boston dentist William Wharton, who had been experimenting

with ether as an anesthetic, persuaded Dr. Jacob Bigelow and Dr. John
Collins Warren, two of the world's most prominent surgeons, at the
Massachusetts General Hospital to try his preparation to relieve pain
during surgery. While medical students watched, Morton administered
ether to a patient using a glass vial and a breathing tube.
John's Collins Warren removed a tumor in this Boston laborer's neck.
The patient woke up minutes after the surgery and said that he felt
some scratching but hadn't felt pain.
It was such a momentous occasion that Dr. Warren called the surgical
team and the patient back for a photograph. Dr. Bigelow wrote a report
that was published in the Boston Medical and Surgical Journal, a
forerunner of the New England Journal of Medicine. Probably the most
famous article in the journal's 200 year history, it was followed a month
later by Dr. Warren's description of ether anesthesiology in several
more cases.
But what's so surprising is that some of the properties of ether have
been known for half a century. Why was it not immediately applied? I
think it just has to do with the fact that surgery was considered to be
essentially painful and that the relief of pain was not seen as a
dominant goal.
In a matter of months, the published reports of the successful use of
ether inspired enough surgeons that it became standard practice.
Putting it into the public domain where other clinicians could observe it,
begin to learn from it, and try it themselves was crucial. The
introduction of ether anesthesia in the mid-1840s really revolutionized
the practice of surgery and opened up the possibility of working the
body and working in the body in ways that were just not possible before
that.
Even with anesthesia, surgery remained extremely dangerous with a
high mortality rate.
Early in surgery, many of the patients could have an operation, let's say,
but would die from infection, and we didn't understand what the cause
of the infection was. There were many debates about what caused
patterns of disease and how they would be understood: was disease in
the air, in the body, or in something you couldn't see?
In 1847, a Hungarian physician ignited some ice and made a
breakthrough in the battle against infection. He had discovered in
childbirth that if obstetricians and midwives washed their hands, they
could prevent child bed fever, or puerperal fever, the biggest killer of
mothers in child delivery in hospitals around the world.
Unable to offer a scientific explanation for his findings, Semmelweis
published them, but not in a way that could be verified by his peers. He
was insulted by calls for proof and lashed out at his detractors, dooming
his discovery. He was a failed genius because he could observe what he
was doing and recognize something that needed to be done, but he
never actually published it as a study to demonstrate to his colleagues
in a respectful way why what they were doing needed to change.
Ten years later, French chemist Louis Pasteur presented his research on
fermentation, arguing that microorganisms in the air caused infection.
His work marked the birth of bacteriology and established the germ
theory of disease. In 1865, the British surgeon Joseph Lister learned
from a paper by Pasteur that certain chemical agents killed
microorganisms. Lister recognized that carbolic acid could lower the
bacterial count, and he extrapolated from that to say, Well, while we
put it on our hands, why don't we aerosolize it in the operating room or
spray it on our wounds and see if that decreases the risk of infection?
Which it did. Lister reported in The Lancet that he could reduce
infection. It was roundly dismissed by many surgeons, including the first
report in the New England Journal that alleged him to have been deeply
mistaken. Lister's articles and his approach were controversial because
they imply that it was surgeons who brought these infections into the
surgical theater. It was really at least two to three decades of debate
about what's the best approach and whether there are microorganisms.
Eventually, there was a shift from antiseptic to aseptic surgery, and that
is the paradigm today.
What the discovery of anesthesia and the discovery of how to prevent
infection allowed us to do was more ambitious operations for the first
time. We don't have a recipe for surgery. It can go wrong and change in
unexpected ways, and what you need is a team that can work together
to handle the unexpected. There are more than 150,000 people who
die within 30 days after surgery, and if we can put this over here, this
has been a kind of invisible epidemic here; we have five times as many
people dying after surgery as died after road traffic accidents.

To make surgery safer dr. Gawande has pioneered the use of a checklist
like Pilots use that ensures surgeons don't forget key life-saving steps.
there's a checklist before anesthesia. It begins with the introduction of
the surgical team. do we have blood available have we given an
antibiotic on time we want the anesthesiologist to talk about the
medical issues that that we have to be aware of, the nurse to talk about
equipment and any questions that they may have, okay and only then
going ahead with the incision. To our surprise the checklist has had
dramatic effects in reducing deaths. We've gone from a place where
two generations ago we had only a handful of therapies that were
highly effective in the pre penicillin to one today where we have 6,000
drugs, we have 2,500 surgical procedures, 1,500 non-surgical medical
procedures that you can do. Now being able to handle the extreme
complexity at such a large scale with so many people that we take care
of has become our major challenge.
dr. Gawande ends eilene’s surgery with the sign-out checklist. the
nurses account for all the sponges and surgical instruments. the team
confirms what happened in surgery. I like to pretend I'm a young
surgeon I've been in practice now this is my ninth year during that time
already there are changes from what I learned even more emphasis on
minimally invasive techniques.
The old dictum that was popular when I was coming along was it you
know surgeons were physicians who operate and always liked that
phrase because that you know we think as a doctor first and then
intervene surgically if we have to. I think conservatism is a good thing
for surgeons.

Targeting Cancer: The Story of Leukemia

How many have cancer in the u.s. today, no man knows. what causes
this is one of the riddles men puzzle over in their laboratories to a
lifetime.
In the 1930s a diagnosis of cancer was always grim. we had surgery and
surgeons were perfecting their technique trying to take out more and
more a tumor and then you had radiotherapy but real therapy was very
crude in the 1930s. and with cancers like leukemia that are
disseminated in the blood there was no cure.
Because you couldn't give radiation to the whole body without killing
the patient and you couldn't obviously do surgery with the whole body
involved. In a basement lab at Children's Hospital in Boston a
pathologist named Sidney Farber was trying something new he was
looking for a way to kill childhood leukemia with chemicals. Sidney
Farber was not well-loved in Boston. He was thus autocratic Stern kind
of person which tends to put people off. So nobody wanted to give him
facilities to do what he wanted to do because they thought it was crazy.
in 1946 a colleague of Farber's a chemist named yella Pro goddesu
barão had shown that folic acid could cure a certain kind of anemia. dr.
Farber thought well maybe this could be effective in acute leukemia
since they were both blood disorders. he obtained some folic acid from
dr. Subaru and injected it into children with acute lymphoblastic
leukemia and always fatal disease. he was a pathologist. he was not
trained take care of people let alone little people so you can imagine
the attitude toward what he was doing. The experiment backfired the
folates only stimulated the cancer cells. well, that sounds like a disaster
and today of course would be a disaster but of course that gave him
another idea. naturally he said well if folates increase the growth why
not try anti folates. This time Farber got an anti folate a drug called
aminopterin and gave it to 16 children with ALL. and much to his
surprise this time instead of stimulating leukemia, it massively
destroyed the leukemia.
it was unprecedented that you could see a remission from giving a
chemical division. it was written up in the New England Journal of
Medicine where it stirred a small controversy because the patient's all
relapsed you know lots of papers written by very famous hematologist
who said you shouldn't do this because you know you may think it's
really a terrific thing but you're still patients are all dying and so it
doesn't mean anything but meant something to people who are
thinking if we're going to make progress in cancer we had to do
something about these cells that are circulating around the
bloodstream.
In 1948, Farber helped the Jimmy Fund which would raise millions for
the cause. Dollars poured in and went to new cancer research centers
and new cancer drugs like methotrexate, a relative of aminopterin that
was easier to produce. The drugs were all highly toxic and they worked
in a crude way killing healthy cells along with the cancer cells.
sometimes patients died from the side-effects.
we didn't know how to use them we didn't know which patient to use
them in.
in Memphis Tennessee at a newly opened Children's Research Hospital,
a team of clinicians were studying how to use chemotherapy drugs
more effectively. the hospital is opened and dr. Pinkle and a few early
colleagues got together and systematically thought about how can we
develop a protocol that might address all the problems seen in the 50s
and really try to produce curative therapy.
they tried longer chemotherapy treatments in different combinations
they added cranial radiation, they gave the methotrexate directly into
the spinal column, and within ten years they were curing half of all
cases of ALL. it was progress but what about the other half? what was
different about these children and their cancers in the 1970s scientists
would find out as they began to unlock the mystery of the cancer cells.
when we had deciphered these groups called T cell leukemia b-cell
leukemia or B progenitor cell leukemia they were entirely different
diseases we've been grouping them and treating them all the same they
didn't respond all the same.
the field of cancer genetics would continue to evolve over the next
thirty years revealing hundreds of variations in almost every kind of
cancer. two boys in Phoenix Arizona illustrate the importance of these
variations. Adam O'Conner was diagnosed with a leukemia called pre b-
cell ALL when he was four years old he was treated with the standard
methotrexate based regimen it worked.
I've been cancer-free for 11 years I do triathlons it's just an amazing
thing that I could be a disease like that and feel completely normal so
did your Christmas presents come yet has a yellow maeda has the same
pre b-cell ALL and got the same methotrexate based regimen but after
three years his cancer came back cancer genetics revealed why when
we looked back at house leukemia tried to sort out why was it his
leukemia that came back so fast and so widespread it was determined
that he had a chromosome abnormality that actually now is considered
a very poor prognostic factor.
ALL like most cancers is the result of several chromosomal
abnormalities an adult cancer called CML for chronic myeloid leukemia
has just one abnormality the Philadelphia chromosome. the
abnormality was due to a translocation from two genes one piece of the
chromosome broke off went to another one and where the two joined
they made a new gene and it's that gene that's driving the cell division
now it's just saying go go go go until the patient dies of leukemia. every
single patient has the same oncogenic abnormality the fell off a
chromosome and most other cancers are far more heterogeneous.
at his research lab in Portland Oregon, dr. Brian Druker was working on
a way to target just this one mutation. if cancer is sort of like a light bulb
being stuck on, chemotherapy was let's just take a baseball bat and
knock out the light, and I looked at that and said we've got to figure out
why that lightbulbs stuck on, and if we can figure out why it's stuck on
then we can shut it down, and we'll leave everything else intact. this is
the we used to dream of when I started in the field you could actually
have this kind of specificity a lot of people said well we tried that we've
thought about it it's never gonna work just get a bigger baseball bat.
in 1995, Judy Orem learned that she had CML and was told that she had
three to five years to live. she was given the standard therapy a drug
called interferon. the interferon really didn't do much for me I was on it
for three years the best I got was down to 60% Philadelphia
chromosome which was not very good.
dr. Druker was testing a class of drugs that would target just the
Philadelphia chromosome he tried one called imatinib also known as
Gleevec. We gat patients donate some of their leukemia cells and we set
them up in some assays with the drug and we actually found that their
leukemia cells didn't go out in our cultures but they're normal cells did
and so it was absolutely clear that we were killing leukemia cells and
not harming normal cells in cell lines animals and impatient samples
and that gave me great confidence that we needed to move this drug
into people and see if it would work.
I have a friend who called me and said Judy they announced on the
radio and it was in the newspaper that the Leukemia Lymphoma Society
had given dr. Druker a translational grant to take a study from you know
the petri dish to get ready for human trials on CML and I think you
should get your name in there. she did and when the first clinical trial
began in 1998 she was on it as patient number nine. I started feeling
better my appetite back my sense smell I put on weight.
within three months the imatinib had nearly eradicated her CML with
no side effects. they were able to actually get rid of the Philadelphia
chromosome when the interferon I got down to 60% Philadelphia
chromosome on this I got down to 5%. Judy was one of the people that
I remember and always referred to when people say when did you
know your drug worked. word spread quickly in the CML community
patients began to band together and realize that as a rare disease they
could actually help one another navigate through the channels get their
doctors to refer them get themselves refer and share information about
the disease when nobody had information before. people were soon
lining up for the Phase two trial with this miracle drug but there was a
problem. Novartis said we're not sure the drug is going to make enough
money for us if it's going to really hit enough people we might stop well
finally the Phase two trial went forward with great success results were
reported in the New England Journal of Medicine in April 2001 it was
one of the paradigm changing publications because it is the first proof
of principle of targeted therapy.
just one month later imatinib was approved for human use by the fda.
for this one cancer at least it was the holy grail that scientists had been
looking for since the days of Sidney Farber.
the last results you probably saw yeah never everything was perfectly
stable there's absolutely no question that the work I did was built on
the shoulders of giants fifty years after Sidney Farber's work we have a
huge understanding of the genetic basis of cancer and even some the
true biochemical and metabolic differences between a cancer cell in a
normal cell and all those are becoming amenable to target.
it's a promising time to be an oncologist you'll get your chemo for five
days. there has been incredible progress over the last four decades.
forty years ago it was a death sentence and barely any children would
survive their acute lymphoblastic leukemia now we are curing leukemia
with a cure rate of almost 95%. huzi Elle's case is a tough one while
some children with ALL have the Philadelphia chromosome now a
druggable target he has an abnormality which has not yet been
targeted and so his doctor relies on larger doses of standard
chemotherapy. when hacia relapsed we knew that it was an aggressive
type of leukemia and so at that point we decided that in order to give
him his best chance of cure we would perform a bone-marrow
transplant. so we will use his ten year old brother as his matched joning
sibling so we're hoping that these donor cells are gonna work and cure
his leukemia. I think they will I have a good feeling we had to see
members on instance forget you as advances in research and therapy
continue the hope is that all cancers will one day become if not curable
chronic and manageable diseases. now we have lots of patients who
have been treated and are cured and I think as we go in the future
you're going to see more and more patients followed by the primary
care physician and I think it's a good thing.

The Plague of our Time: The HIV/AIDS epidemic

Shari Lewis a singer and AIDS educator has been hiv-positive for almost
25 years I went for the blood test for my marriage license and three
weeks later on April 12th 1987 my 33rd birthday three months before
my wedding day the doctor called and told me on the phone that I was
in fact positive.
at that time it was practically a death sentence. the first time I
encountered patients with HIV was during my residency training in
Boston in 1985. most of the patients had very advanced disease and we
didn't have any treatment. people didn't make it out of the hospital.
in the late spring of 1981 on my desk was the June 5th issue of
morbidity and mortality weekly report five gay men from Los Angeles
very very sick with a pneumonia that you only see in people who are
immunosuppressed. one month later was the second report of 26
individuals again curiously all gay men from LA San Francisco and New
York all presenting with this unusual syndrome of not only
Pneumocystis pneumonia but several of them had Kaposi sarcoma and I
can remember thinking my goodness this is something really new and
really scary.
physicians even in infectious diseases and an internal medicine were
quite afraid the first patient that was admitted the reaction of the staff
to this individual was as if he were carrying smallpox.
it was not recognized at all at the time of the New England Journal of
Medicine paper in late 1981 for the potential seriousness of what it
really was.
it was very frustrating because we were seeing infections in a single
individual in a fashion that was just overwhelming and disfiguring we
had to deal with end of life issues on a regular basis. to make matters
worse the disease carried a terrible social stigma because it was seen
most commonly in gay men and IV drug users. people would say well
you know you deserve this for this terrible life that you're leading. there
was a lot of bad stuff there with regard to stigma intolerance
insensitivity to what these people were going through.
the CDC established in 1982 that the virus was transmitted sexually and
by infected blood to drug users and hemophiliacs but that didn't stop
the speculation misinformation and fear people. believe HIV was
transmitted by mosquitoes or toilet seats or by kissing or eating utensils
or drinking from people's water glasses all sorts of things.
in 1984 French and American researchers discovered the cause of AIDS
it was a retrovirus they called human immunodeficiency virus or HIV
that attacked the immune system and integrated into the genome of
our cd4 cells. within a year a blood test for AIDS was developed it
revealed that the virus could lay dormant for years suggesting that we
were seeing just the tip of the iceberg.
even those of us who were in it from day one were shocked by the
enormity of the problem.
by this time AIDS was spreading exponentially in developing countries.
my first experience with HIV as a fission really happened when I was a
medical student in 1986 I was shuttling between Harvard and Haiti at
the time in the epidemic had hit the urban areas before we knew it you
know we had patients of our own from central Haiti.
it was a very different epidemiology than what we saw and then I'd say
AIDS was incapacitating to men and women and especially women was
clear that it was more readily transmitted from men to women than
women and men.
the stigma of AIDS was different in the developing world as well. way
beyond the question of its mode of transmission there is always a
stigma associated with any wasting consumptive disease that takes
young lives. farmer and his colleagues at Partners in Health had to beg
for resources to care for the AIDS patients and their families coming to
his clinics.
people would say well you can't throw money at it well please you
know throw something just cold hard cash because that could bring in
human resources and help build up health systems.
in spite of the of the growing severity of the epidemic in the US and
globally the federal government was slow to respond. President Reagan
didn't even mention the word for years and years and years thousands
of people had died. the gay and hiv-infected communities mobilised to
demand care and affordable access to the first HIV drug AZT the AIDS
coalition to unleash power act up took to the streets. they did some
outrageous things that are now part of the manual of activists activities.
if you listened to what they were saying they were really making sense.
they were developing drugs and those folks instead the benefit the
most from the drugs had no role of influence that process. we decided
that we were going to force them to know that we were there and as a
result of that we put her face days and we refused to go away.
and that really started off what turned out to be now intensive
involvement of activists and virtually every phase of what we do with
hiv/aids. AZT extended lives but drug resistance always emerged by
1994 the number of AIDS case s in the u.s. had surpassed 400,000. AIDS
had become the leading cause of death in Americans ages 25 to 44. and
pregnant women infected with the virus were passing it on to their
babies.
one of the biggest breakthroughs in the history of HIV prevention is
signified by AIDS clinical trials group or ACTG o76 if you treat a pregnant
woman with AZT during the pregnancy and during delivery and then
treat the baby for a certain period of time you can dramatically
decrease the likelihood of transmissibility.
the OSM e6 trial was a bit of a personal epiphany for me because a lot
of the debate back then was about prevention versus care.
the debate was where should we put our resources since we don't have
treatment then we put them all into prevention but again that made it
sound like we had good prevention technologies which we didn't where
it was no vaccine the main prevention strategies included condoms
which were usually controlled by men and so called abstinence
approaches. so along comes oh seven six at O seven six is about a drug.
the use of AZT to prevent mother-to-child transmission introduced HIV
drugs to the developing world and was the first truly effective step in
combating aids in resource-poor settings but there was still no durable
treatment.
Phil Wilson had been diagnosed with AIDS in 1982. they're often days
when I would spend the morning taking care of my partner followed by
a doctor's appointment for my own health followed by visiting another
friend and a hospice care followed by attending a funeral of followed by
a rally followed by preparing for a meeting with a policymaker or an
elected official followed by taking care of my again.
in the early 90s researchers were making progress approaching the
virus from multiple directions. do one drug like AZT it was good for a
short while to suppress the virus and then the virus figured out a way to
escape it so it was very clear that we had I get combinations of different
targets trials involving several antiretroviral drugs targeting the viruses
protease enzyme began in the mid 90s. word of these promising agents
spread rapidly through the HIV community. finally a string of
breakthroughs. the AIDS clinical trial group 3:20 was the first study to
show the full clinical benefit of highly active antiretroviral therapy
heart. while we were very actively clinically testing different
combinations of drugs we reached the point where for the most part
the virus couldn't escape that you kind of boxed it in. I was involved in
some of these trials as a site investigator and when we started to see
the patient's clinical status improving it wasn't so clear what was
happening but after patients had been on the study for four to six
months we really started to notice that nobody was getting sick.
many of us experienced that Lazarus syndrome where we were on
death's door I was in the intensive care unit and a coma and the doctors
had given me less than 24 hours to live I went on heart and got better
and the rest I guess is history in the making but the drugs were
expensive and it was hard to get them to the developing world so we
went to the manufacturers the drug and said you know give us a hand
help us out and a number of drug companies did get involved so we
went from $10,000 per patient year to about 1,200 it wasn't until we
went to the generic manufacturers and said we need not just thousands
of people and care we need millions and that's what really permitted
the scale-up that's under hundred dollars per patient per year those
steps have saved millions of lives I've had now a number of patients
born with HIV who are adults and have children of their own and did
not pass on HIV to their children there was no possibility of putting
millions of dying people on therapy without the Global Fund and
PEPFAR President's Emergency Plan for AIDS relief people really
surprised when the Bush administration decided to launch the largest
global health effort in history dr. Tony foutch II was working with the
White House to make a plan but first it had to get passed the Office of
Management and Budget he called a small group together including
Paul Farmer to go to Washington to make the case he said I'm sending
you in to the White House as my expert witnesses and you know I
thought that sounds scary to me but we knew what we were doing was
right it's just that we had so little experience and Tony knew that if
PEPFAR became a major program that we could break that cycle of
poverty and disease and strengthen health systems which is not a very
attractive sexy thing to fund but critical to survival of lots of people with
other problems beyond AIDS the meeting was held in late 2002 when
we said but we know it'll work we've already done it we have people
come back from the dead then the White House staff said well but
that's because you're an infectious disease doctor and I said no no this
is care delivered by community health workers and my Haitian
colleagues I would say that that small cohort of first patients from Haiti
had a big impact challenges remain in the developing world only half of
the 410 million people infected with HIV who should receive
antiretroviral therapy are actually getting it.
in Los Angeles 90% of judi couriers patients are doing well on their
treatment. Shari Lewis started antiretroviral therapy in 1997 when she
began to have sim it changed the direction of my life which of course
was supposed to be a very short one but thankfully it's been a full life.
that you know they've been everything some of the complications that
we see in our patients who've had HIV for a long time are things like
osteoporosis cardiovascular disease we're trying to sort out really to
what extent these are due to the normal aging process or due to side
effects of HIV medications or chronic HIV infection. still the progress in
the last 30 years is undeniable good
the AIDS story is actually a success story and I'm not sure everybody
knows that it's a scientific success it's a development success and it's a
delivery success we've delivered the medicines now we haven't done it
good and well enough but I think it's huge that you have millions of
people. research is to have the voice of the community and to have
people pushing hard for what we need to do I think it's made us all
better we are in the throes of needing to go from a system that's
trained hired and rewarded people for being Cowboys and trying to
become one that trained rewards and hires people to be like pit crews
working together for a patient imagine trying to read the New England
Journal of Medicine in rural Africa you know 25 years ago and and now I
can tell you that my colleagues in Rwanda and rural Haiti and they have
access to journals they have access to search capacity right there in
these rural regions that that's huge you you .