|
| Credit: Shutterstock |
|
We are in the midst of a scientific revolution,
changing from the long-established practice of teaching patients to live with
disability to the new field of regenerative medicine that utilizes stem cells
and other approaches to regenerate tissues and restore function. As with all
revolutions, regenerative medicine is encountering opposition on many fronts
and for many reasons. Some objections are moral, others scientific. Some people
object to a particular approach because they think it is scientifically unsound,
while others have a vested interest in a different methodology or a favored
cell or mechanism. The lack of sufficient funding will fuel these attacks
because projects and careers are at stake.
This revolution raises
new questions and requires new strategies. For example, scientists are trying
to figure out which lessons from the past will inform the future. In their 2013
book Decisive: How to Make Better Choices
in Life and Work, Chip and Dan Heath identify several ways that people get
trapped when making decisions: “Research in psychology has revealed that our
decisions are disrupted by an array of biases and irrationalities: We’re
overconfident. We seek out information that supports us and downplay
information that doesn’t. We get distracted by short-term emotions. When it
comes to making choices, it seems, our brains are flawed instruments.
Unfortunately, merely being aware of these shortcomings doesn’t fix the
problem, any more than knowing that we are nearsighted helps us to see. The
real question is: How can we do better?”1
One of the shortcomings that Chip and
Dan Heath stress is the human tendency to get trapped in binary (either/or)
thinking. This raises a query: What are some ways in which moving beyond binary
thinking could change the future of science? Let us suggest four areas to
consider.
Collaboration and Competition
It’s
the lone researchers who generally explore scientific frontiers, but groups of
people with various areas of expertise come together to consolidate advances. As
new knowledge arises, these groups solidify standards that provide the platform
for the next frontiers.
The
battles between Jonas Salk and Albert Sabin to find a vaccine for poliomyelitis
are well documented. Each scientist was driven and fervently believed in his
approach. Funding from the National Foundation for Infantile Paralysis fueled
the competition, and secrecy hid fundamental errors that openness might have quickly
revealed. The competition strengthened each researcher’s commitment to his
approach, but it perhaps caused a significant delay in finding a vaccine when
both Salk and Sabin initially ignored the findings of Dr. Dorothy Horstmann,
the woman who discovered the actual path of the viral entry.2
On the other hand, an effective model
of collaboration functioned between 1993 and 1996, when the National Institutes
of Health (NIH) funded work on the Multicenter Animal Spinal Cord Injury Study
(MASCIS). Eight leading spinal-cord-injury laboratories in the United States
worked together to develop and validate the first standardized rat model of
spinal-cord injury. In addition to developing the model, MASCIS scientists developed
outcome measures such as the Basso, Beattie, Bresnahan (BBB) locomotor scale
and white-matter sparing, both of which became standards in the field. The
first project of its kind funded by the NIH, MASCIS proved that people in
different laboratories can work together to develop approaches and to standardize
procedures, thus enhancing the work of each of the individual researchers.
The
current model of individual principal investigators competing with each other
for funding, and the consequent lack of collaboration, not only is expensive
and inefficient but also forces scientists into undesirable binary thinking
that invariably accompanies competitive endeavors. What your competitor is
doing automatically becomes off-limits. A much better approach to developing
new scientific discoveries would be to offer increased funding of projects that
both enhance collaboration and stimulate individual initiative.
Biology and Technology
Biotechnology
has become
the buzzword of the 21st century; an entire industry has arisen around the
term. But biology and technology don’t always work well together. One example
is the dichotomy between the electrical stimulation and cellular
transplantation approaches to restoring function to people who are paralyzed.
Implemented by engineers who think in terms of electrical current,
voltage, and resistance, a whole field has been built around functional
electrical stimulation (FES)—using computers to deliver electrical signals to
muscles and treating human muscles like robotic components. The film RoboCop exemplifies the thinking and
limitations of this approach. In contrast, cellular transplantation is the
brainchild of biologists, who think in terms of synapses, neurotransmission,
and metabolism. As with FES, an entire industry has grown up around the concept
of cell transplantation. Fueled at the end of the 20th century by the discovery
of stem cells, this field has been dominated by paranoia and fanciful thinking
illustrated in the film Star Wars: The Clone
Wars (2008).
Biology and technology must work together in practical and
realistic ways to restore meaningful function based on the best available
technology and understanding of biology. A recent example provides a clear
illustration of a fruitful marriage between biology and technology. Each field
provides a best-of-class solution to the problem of restoring function after
spinal-cord injury.
Many researchers have shown that the spinal cord can regenerate.
For example, Lu et al3 demonstrated that rivers of axons can grow
across the transection site of a rat spinal cord if you implant mesenchymal
cells to form a bridge, inject the response-element binding protein cAMP to
motivate neurons to grow the axons, and induce the neurons on the other side of
the gap to express growth factors and “come hither” signals. Likewise, Liu et
al4 showed that silencing a single gene called PTEN can stimulate
rivers of axons to grow across the injury sites in mouse spinal cords.
The problem was that the rats and mice did not recover motor function
even though thousands of axons grew across the injury site and made connections
with neurons above and below it. It was fairly obvious why function did not
recover. The regenerated axons were new, and they probably were not connecting
to the neurons in the same way the old axons had. Thus, the brain had no idea
which “buttons” to push to move specific muscles or how to interpret incoming signals.
Much evidence suggests that intensive locomotor training is needed
in order to restore function. In fact, the most successful mobility training
programs for those with spinal-cord injury are those that involve prolonged
repetitive activation of desired movements as often as six hours a day, six
days a week, for six months or more. Such intensive training is not only
expensive but also unavailable to the majority of those who would need it.
Why is such intensive training necessary for functional recovery? It
turns out that learning requires repetitive activation of synaptic connections.
In Donald Hebb’s5 book, The
Organization of Behavior: A Neuropsychological Theory (1949), he proposed that
timing of synaptic activation is responsible for learning. Specifically, Hebb said,
“When an axon of cell A is near enough to excite cell B and repeatedly or
persistently takes part in firing it, some growth process or metabolic change
takes place in one or both cells such that A's efficiency, as one of the cells
firing B, is increased.” Sometimes rephrased as “Neurons that fire together,
wire together,” the Hebbian principle has become a leading theory of neuronal
learning. The formation and consolidation of synapses or connections requires
synchronized activity from sensory and central sources. Intensive exercise can
achieve such synaptic consolidation, while desynchronized activation weakens it.
Electrical stimulation is one way to induce synchronized activity
for spinal-cord injury. Today most people carry in their pocket or purse more
computer power than what once filled an entire room of mainframes.
Brain-to-machine interface has demonstrated the ability to control and deliver
electrical stimulation synchronized to desired activities and thereby increase
synaptic consolidation and learning of regenerated fibers. Therefore, a
combination of cell transplantation and electrical stimulation is the best way
to restore function when neither can do it alone.
Regenerated axons are not a repaired nervous system but a new one
in which new neuron-to-neuron and neuron-to-muscle connections must be learned.
Initial studies show that transplanting umbilical-cord-blood stem cells in
combination with intense physical therapy restores walking in people with
spinal-cord injury. But the cost would be prohibitive for large numbers of
people to participate in months-long walking programs. However, what if people
could receive cell transplants and walk two hours a day in addition to
undergoing electrical stimulation that allows them to continue to “walk” while
they sleep? Injected stimulators such as the rice-size BION raise this
possibility.
Hope and Realistic Expectations
The story of stem-cell advocacy is
relevant to the balance between hope and realism. Celebrating the passage of
stem-cell legislation in New Jersey in 2003, Commissioner of Health Fred M.
Jacobs, M.D., J.D., proclaimed that stem-cell medicine was the most significant
paradigm shift in the 40 years he had been practicing medicine. Newspapers
heralded the advance, and community advocates believed that with the exception
of restrictions imposed by President George W. Bush, the way was clear for
miraculous cures for devastating diseases.6
In a movement called Quest for the
Cure,impatient activists worked
together to pursue stem-cell legislation at the state level. In December 2003
New Jersey passed S1909/A2840, and California’s Proposition 71 followed in
November 2004. Each of these bills, and others that followed, provided avenues
for funding stem-cell research within its respective state. During a subsequent
backlash, other states increased restrictions on—or entirely prohibited—fetal
and embryonic stem-cell research.
On March 9, 2009, excitement filled
the room when, in front of many disabled and ill people and their families,
newly elected president Barack Obama signed an executive order lifting
restrictions related to human embryonic stem cells. The president proclaimed, “Today,
with the Executive Order I am about to sign, we will bring the change that so
many scientists and researchers; doctors and innovators; patients and loved
ones have hoped for, and fought for, these past eight years: we will lift the
ban on federal funding for promising embryonic stem cell research. We will
vigorously support scientists who pursue this research.” Later, when the order’s
official guidelines were released, scientists were disappointed to discover
that the new policy was more restrictive and onerous than the previous one.
Even more disappointing was the fact that no increased funding was to follow.
Two years earlier, Shinya Yamanaka’s
discovery that skin cells can be reprogrammed to become embryonic stem cells
called induced pluripotent stem (iPS) cells had changed the field and had made
it unnecessary to harvest fertilized eggs in order to obtain embryonic stem
cells. To date, no iPS cell has been tried in humans because of fears that
these cells can produce tumors. However, the discovery established the
principle that pluripotency is genetically programmed. Further recognition of
the discovery’s significance came when Yamanaka received the Nobel Prize in
2012 for Physiology or Medicine.
The suppression of embryonic-stem-cell
research did lead to a renaissance of
studies of adult stem cells. This soon resulted in over 4,500 clinical trials
involving stem cells in the United States. The field of stem-cell therapies has
turned 180 degrees from embryonic stem cells because pluripotency is not as
desirable as originally thought. In fact, most scientists and clinicians
consider pluripotency to be a dangerous property that must be eliminated before
cells can be transplanted. For example, Geron Corporation obtained permission
from the Food and Drug Administration (FDA) to transplant embryonic stem cells
into people with spinal-cord injury, but only proving that less than one in a billion
transplanted cells were pluripotent.
Pluripotency—the ability of make many
kinds of cells—is a dangerous property if not controlled. Stem cells that find their
way into the spinal cord to make a hair or a toenail or to penetrate a tissue—but
end up causing a tumor—are harmful to the point where the human body has evolved
to suppress pluripotency. An adult stem cell can behave like a stem cell only
if it finds a niche of cells that tell the stem cell exactly what to do, which
is why it is so difficult to grow stem cells in culture. Nature has developed
ways to reduce the dangers of stem cells by forcing them to produce the correct
type and number of cells in response to tissue requirements.
Hype comes from ignorance. When
embryonic stem cells first were discovered and grown in culture, we did not
understand stem cells and the implications of pluripotency. Scientists were
excited about the possibility of growing any and all sorts of tissues from
embryonic stem cells. The public regarded embryonic stem cells as a panacea.
Religious conservatives believed that allowing embryonic stem cell research to
proceed would lead to the practice of killing fetuses to treat adults. With more
knowledge and greater understanding of the biology of stem cells, we now have a
more balanced approach to stem cell therapies.
Real hope comes from knowledge and
understanding. For example, we know from animal studies—and hopefully soon from
clinical trials—that the spinal cord can regenerate. At the same time, our
expectations are tempered by the observations that animals do not recover
function after regeneration and that intensive exercise and training are needed
to restore function. But lest overhyping hope sow the seeds of its own
destruction, hope must be coupled with honest realism.7 In the
absence of understanding, scientists would do well to under promise and over deliver.
Compassion and Caution
Each potential treatment raises the
question: When is "too soon," and when does an overly conservative approach
perpetuate human suffering? Are large animal studies always required before
people can be studied, and to what extent are double-blind randomized trials de
rigueur? What data are sufficient to move forward with clinical trials? When is
a situation so critical that immediate action is essential?
The present Ebola virus disease (EVD)
epidemic has brought this debate into focus. As deaths mounted, ZMapp (Mapp
Biopharmaceutical, Inc., San Diego), a potential treatment untested in clinical
trials, was given to six patients. Three lived, and three died. According to
the World Health Organization (September 2014 Fact Sheet N103), the average
fatality rate for untreated EVD is 50 percent, with a range of 25 to 90
percent. So, what, if anything, was learned? Did a sense of urgency overcome
scientific rigor? Should it have? Now one idea is that the blood of EVD
survivors might impart immunity to patients, and transfusions are being given
to patients without meticulous study.
The question of timing raises the
important issue of whether there should be different standards for situations
like the AIDS epidemic of the 1980s and the present EVD crisis—in which death
is a highly probable outcome—or for conditions like spinal-cord injury, in
which people are paralyzed but stable. Should victims of the former have
fast-track access to untested potential treatments while victims of the latter
are made to wait through a full clinical-trial process? Should there be different
criteria for children as the enterovirus D68 (EV-D68) respiratory illness
spreads across the United States?
One danger arising from delay in
committing resources and manpower is the burgeoning industry of false promises.
Whenever new possibilities arise, such as stem cells and clinical trials,
so-called clinics spring up like mushrooms and offer these treatments—or claim to offer them—without waiting for
trial results. For instance, the black market for the blood of EVD survivors
was flourishing almost before the newsprint was dry. Unscrupulous opportunists
lie in wait to take advantage of the desperation of the afflicted and their
families.
Under what circumstances should
compassion supersede caution? Should the definition of “compassionate use” be
expanded to offer people the option to obtain treatments approved by the FDA
for Phase III trials but at non-trial sites by companies in exchange for cost
of the therapy? It behooves the scientific community to develop guidelines to
balance the urgency of impending death with the dreams of those who would be
healed.
Another principle advanced by the
Heaths in their book Decisive is that
of multitracking options—that is, keeping all options on the table. Politics,
fear, and mistrust raise the “slippery-slope” argument, which too often results
in the closure of pathways that may be beneficial. For example, would we have
safe nuclear power today if fear had shut down nuclear research? Would adult
stem cells have been discovered or well understood if all embryonic-stem-cell
research had been terminated, as some people wanted?
There will always be tension between
mechanical and biological approaches, between hope and hype, and between
caution and risk—the struggle surrounding whether to test something new as
early as possible despite the inherent danger or to wait too long at the
potential expense of human lives. Debates about funding short-term immediate
therapies or long-term potential breakthroughs will continue to rage. Are we
open to radically different changes, such as shifting from developing each
vaccine from scratch to the “chassis approach,” used by VaxCelerate, which cut
time and money for a Lassa fever vaccine from several years and billions of
dollars to four months and less than a million? Critics will continue to question
practices such as spending money and using manpower on heart transplants from
pigs and baboons; isolating stem cells from urine; 3-D “printing” of organs;
DARPA’s ElectRx program, which may give humans self-healing powers8;
and quality of life issues like that raised by Ezekiel Emanuel in his recent
article “Why I Hope to Die at 75”9: How long is too long to live?
As we look to the future, we can
learn from past revolutions. Experience enables us to anticipate. During the
battle over polio vaccines, Dr. Thomas Rivers reminded the researchers,
“Nothing is sacred in science; you give up the old when you find something new
that is better.” When we fail to follow promising leads, we freeze ourselves to
the obsolete, shut-out the critically important, break our foundational
commitment that science exists to help people. Every path will be bumpy, and
many roads will be dead ends. There always will be scientific and moral
questions without easy answers.
But the greatest ethical travesty
would be to stop the science.
