Sep 082016

The Zika virus has captured headlines for its horrific effects on fetuses. Everyone is well aware that the virus spreads through mosquito bites.  However, less well known is that Zika can also spread through sexual contact and blood transfusions. Since transfused blood is a frequently utilized component of modern medicine, keeping the blood supply free from Zika is critical to prevent its spread.  It is with this goal that the FDA has recently updated its recommendations stating “all donated units of blood should be screened for Zika Virus” (August 26, 2016). This prudent recommendation is just the latest attempt to keep the blood supply safe from nasty infections. Any donated blood is already being screened for diseases such as HIV, hepatitis B, hepatitis C, and West Nile virus among others. Since the basis of transfusion-transmitted disease is infected donors, it begs the question: Can we create synthetic blood and eliminate donor reliance?

Every two seconds a blood transfusion is performed in the US.  This astonishing demand is met by over 40 thousand volunteer donors rolling up their sleeves and baring their veins every day.  Once drawn from a donor, blood begins a complicated and expensive journey before it can be transfused into a needing patient. Assuring a safe blood product is not cheap, the cost of producing a single, safe red blood cell unit is roughly $250, which equates to nearly $3 billion/year in production costs alone.

The complexity and expense of obtaining a safe, constant supply of this life-saving product are due to three major attributes of blood itself. 1) Blood is not universally compatible among all people, and therefor transfusions require time- consuming tests to assure compatibility. Transfusion of the wrong blood type is often fatal. 2) Blood requires meticulous and extensive safety screening as unsafe blood can transmit many infectious diseases, including HIV 3) Blood degrades when out of the human body; limiting its shelf life.  These characteristics limit our use of blood in the field (ambulances/battlefield), make blood transfusions inaccessible in developing countries, and result in occasional transfusion- transmitted diseases. These limitations could be overcome if a synthetic blood substitute were available. Fortunately, scientists and entrepreneurs are attempting to create such a product.

To better understand the future of blood transfusions we need to delve into their past. Prior to the mid-17th century healers attempted to replace lost blood with animal blood, urine, milk, pitch, beer, and wine; and as expected patient survival was measured in minutes.  In 1667 the first recorded successful human/human transfusion was made.  However, at the time blood types were not understood and predictably the vast majority of transfusions resulted in a quick death.  In 1907 the Czech physician Jan Jansky first described the four blood groups, leading to type-specific blood transfusion and the common use of this life saving procedure.  During World War II the nation and military ran into massive shortages of available blood.  This prompted the US armed forces to begin funding the development of synthetic blood substitutes.  The early substitutes were abandoned after they proved damaging to healthy patients. The public became interested in blood substitutes again in the 1980s when the HIV epidemic hit and blood transfusions were shown to transmit the disease. Some 14,000 people acquired HIV through contaminated blood in the early 80s before testing became available. Faced with the possible end of donated blood, interest in blood substitutes spiked again.

The research in creating synthetic blood resulted in two major synthetic products. The first is known as hemoglobin-based oxygen carriers (HBOCs). Red blood cells, the oxygen-carrying cells present in blood, are able to transport oxygen because they are full of the protein hemoglobin, which helps bind oxygen and allows 70x more effective oxygen transport than water. All the HBOCs use hemoglobin, freed from red blood cells, to carry oxygen.  Intuitively, this makes perfect sense: if the human body is using hemoglobin packed in red cells, and hemoglobin can be made synthetically then a solution of hemoglobin should be able to replace blood.

Were it that simple, we would already have synthetic blood. There are several problems with free hemoglobin in the blood. The first is instability. Free hemoglobin breaks into small protein sub-units that are filtered from the blood by the kidneys.  Quick clearance from the body means only a short duration of oxygen delivery (compared to 120 days for donated blood).  Secondly, hemoglobin interacts with another molecule, nitric oxide (NO), a molecule responsible to dilate small blood vessels. Normally, hemoglobin in red blood cells releases bound NO at the proper time to dilate blood vessels and improve blood flow.  However, free hemoglobin diffuses into the blood vessel walls and strongly binds NO. This causes small blood vessels to severely constrict resulting in a massive spike in blood pressure (think about constricting end of a hose causing water to spray more forcefully). When this constriction happens in the kidneys it can irreversibly damage them.  Furthermore, constriction of the small blood vessels in the heart leads to heart attacks.  For these reasons, free hemoglobin is not a viable blood substitute.

What if you could modify hemoglobin to keep its oxygen-carrying capacity but eliminate its aforementioned short comings?  This is the research that surged in the 80s and has continued until today. The HBOCs accomplish this through different chemical modifications of free hemoglobin.  These modifications include cross-linking the subunits of hemoglobin together (to stop them from splitting up), polymerizing multiple hemoglobin molecules together (increasing circulation time), and there are even chemical modifications to prevent hemoglobin from binding NO (reducing the blood pressure spike). These basic modifications were performed by several companies which showed their product was able to carry and deliver oxygen equivalently to blood in animal studies and in the late 90′s and the early 2000s they began a series of clinical trials.

The first set of trials administered HBOCs to seemingly healthy patients intraoperatively to avoid transfusion with blood. The justification being that these healthy people need only a small increase in oxygen carrying capacity so why expose them to any possible infectious risk if all you need to do is bridge them for a few days.  By all accounts, these trials were successful: Giving an HBOC to a patient undergoing an elective surgery reduced the need for blood transfusions without significant side effects.

When these limited clinical trials were successful, the manufacturing companies went after the multi-billion-dollar prize… using a blood substitute where real blood was impossible to deliver.  That is, delivery of blood to individuals in traumatic situations who could not receive cross-match compatible blood (i.e., in the ambulance, or in the battlefield).  These trials opened up a whole can of worms.  For ethical reasons, patients are required to give consent before beginning treatment with any unestablished method. However, when a patient is incapacitated from a severe trauma they cannot provide consent. Does that mean trauma clinical trials are impossible?  Nope.  The FDA created an “Exception from Informed Consent” for this very reason and the HBOC trials were the first treatments to undergo such “consent free” trials.

These trials were extremely controversial before they started. Instead of consenting an individual, companies/researchers held public hearings in a region and put up billboards instructing individuals how to opt out by obtaining a wrist band.  The trials took place in mostly poor and lower educated areas where residents were unlikely to fully understand the risks. The controversy only grew after the trials because the second set of trials were failures. Several HBOC products showed that they were significantly more lethal than standard treatment (just giving saline) in traumatic blood loss cases. The trial failures along with the hundreds of millions of lost development costs meant R&D funding in the space all but evaporated. In 2008, all previous HBOC trials were reviewed and it came to light that HBOCs showed increased mortality in traumatic settings across the board. A recommendation was made to the FDA to prohibit further phase III clinical trials of HBOCs until the science advanced.

The science has been advancing over the past decade. The most recent generation of HBOCs now perform a chemical modification on hemoglobin known as PEGylation.  This is the process of adding a polyethylene glycol (think non-reactive plastic) directly to a molecule to make it less reactive in the body.  This has resulted in several new trials looking at PEGylated HBOCs to help reduce the need for transfusions and for use in patients where transfusions are not an option.  These trials are more limited in scope than the large trials of the early 2000s.  However, if Zika does infiltrate the blood supply in a meaningful way public interest and funding will flow into this space again.

Of note in South Africa, Hemopure, a HBOC, cleared clinical trials and is available to prevent blood transfusions in elective surgery cases.  One of the major reasons for passing clinical trials there is the frighteningly high rate of HIV in the South African adult population (18.8%!), which means obtaining safe blood is extremely difficult. Furthermore, your dog may get HBOC after trauma as Oxyglobin is approved for veterinary medicine in the United States.

The other major synthetic blood product, known as perfluorocarbons (PFC), is not based on hemoglobin but instead completely synthetic.  PFCs are simple in concept…they are a non-reactive liquid that has the ability to dissolve oxygen at concentration similar to air! This science fiction-like substance can dissolve oxygen so well that it is possible to be submerged in PFC and be able to breath normally. This concept, known as liquid breathing, is demonstrated here on a sedated mouse submerged in PFC.

Liquid Breathing

Liquid breathing with PFC

Treatment with PFCs does not include submerging a human in PFC liquid but rather injecting PFC mixture into their blood that allows them to take up additional oxygen by breathing 100% oxygen. In addition to being completely synthetic, PFCs are also very small, 1/40th the size of a red blood cell.  This allows them to theoretically deliver oxygen at a site where blood cannot flow such as brain tissue beyond the site of a stroke. Sadly, the news is not all good with PFCs.  During a phase III trial, the product Oxygent was shown to increase stroke and was subsequently not approved for sale by the FDA.  Another product, Oxycyte, was not cleared to even undergo phase III trials after results from a phase II dose escalation trial in Switzerland.  If, however you find yourself in Russia or Mexico with a traumatic bleed you could potentially receive a PFC as one is approved in those countries.

In conclusion, making a synthetic blood product is tremendously difficult.  The blood we carry in our veins is the result of millions of years of evolution and not quickly supplanted by a laboratory creation.  However, there is promise in the two current strategies to reduce our reliance on donated blood.  With a massive benefit to society and gigantic financial prize at stake, research should continue until synthetic blood is a reality. Although less studied, I believe a PFC solution is more likely to serve as a future blood substitute given the ease of manufacturing and biological inertness. But until we solve our limitations I strongly urge you to help out your community, roll up your sleeves, and donate blood today!

Nov 032014

Everyone knows their doctor records a myriad of information that objectively monitors our health. What many don’t know is that data in the form of our Facebook friends, tweets, web surfing history, and credit card purchases can ALREADY be used to predict our future health. Furthermore, more exotic data is becoming available daily through the adoption of wearable devices and our omniscient smart phones. Combining traditional medical information and alternative medical data to create an individualized accurate model of our future health needs is the promise of big data in healthcare. The monumental task of collecting and analyzing all this data has already begun by a smattering of companies and governmental initiatives. On the long road to complete data integration, our first important step is electronic medical record interoperability.

Steadily since the turn of the century, hospitals and physician offices have been moving data to electronic medical records (EMR). EMRs have improved healthcare by reducing clinical errors and improving provider efficiency. However, electronic records are not easily shared among providers (interoperability). In a system where health care is fragmented amongst many specialists, this is large problem. In fact, the current method of sharing data is scarily archaic. When a health care provider wants a patient’s external records the following happens:
1) A request is sent via fax to the facility with the record
2) The record holder prints out the record from their own EMR and faxes it back
3) The receiving party scans the documents, or worse, puts them in a paper file that will never be consulted.
It might be hard to imagine that potentially lifesaving information is so poorly managed when all your other electronic information is never more than a click away.

What is the cost of our poorly connected medical infrastructure? A study by the Center for Information Technology Leadership showed that interoperable medical records would directly save $77 billion a year by reducing unnecessary repeat testing. Furthermore, the subsequent savings through better patient tracking and management is suggested to save between $180 and $320 billion a year. The dollar cost, notably exorbitant, doesn’t capture the delayed diagnosis, improper treatment, patient frustration, and morbidity related to lack of adequate information exchange. Making digital patient information available to all providers should be a simple enough task…

So why don’t we have EMR interoperability in the country already? Chief among the reasons is economic incentive; there just hasn’t been any (…until recently). In a system where all test and procedures generate profit health care providers have no financial incentive to seek existing information. They are more profitable by repeating a test. Health care systems where economic incentives exist have perused interoperability. One notable example is the Veteran’s Association hospital system (VA). The VA runs 1300+ hospitals across the country, caring for over 26.5 million veterans. Since veterans can receive care at any VA hospital and the VA budget is limited, the system has an intrinsic benefit to reducing unnecessary repeat test costs. In 1999, the VA system was the first US system to adopt an EMR that shared medical records, laboratory data, and imaging across all hospitals. That’s right…. 1999!! Luckily the affordable health care act is pushing health care systems into accountable care organizations where there is true profit, and therefore incentive in reducing unnecessary testing, promoting interoperability. So…problem solved? Not quite.

Economic incentive alone is not enough. Single payer countries such as England and Canada included do not have 100% interoperability for all medical records despite large economic incentives. Their attempts have been limited by political hurdles as well as America’s second stumbling block, standards. The numerous EMR platforms out there can’t just swap a file to share records like you would to share a PowerPoint presentation. They lack standardization because the main law regulating health care information, the Health Information Portability and Privacy Act (HIPPA), does not spell out a particular data format. Therefore each existing EMR, be it home grown or large commercial package, uses totally different formats. We are in desperate need for the department of Health and Human services to decree a standard EMR format to ease the transfer of data. I liken our current situation to a world that has recently invented railroads but failed to standardize the track.
The challenges facing interoperability are not unconquerable and progress has already been made. Ideally we want a system that seamlessly transfers all available records of a given patient when they show up for care. A major step toward this goal came out of a consortium of many parties in the healthcare industry. This voluntary group of EMR developers, health care providers, payers, is called eHealthExhange. Their main rule states: “Participating organizations mutually agree to support a common set of standards and specifications that enable the establishment of a secure, trusted, and interoperable connection among all participating Exchange organizations for the standardized flow of information…” alternatively stated: follow our standard format and build a secure interface to your patient data. According to their website, approximately 80 major participant health care systems are now compliant, including some of the largest in the country: Kaiser Permanente, MedVirginia, the VA, and I am happy to say my home institution Stanford University. The eHealthExchange allows for seamless access to health information at any of the partners.

Another method to get clinical data to follow the patient is to simply hand over an updated medical record to the patient. There are several programs that let patients build a personal health record (PHR) by manually entering your conditions then having them available via a web interface or mobile app. Among the leaders in the field are Microsoft Health Vault, Dossia, and various apps (also Google Health offered this service before discontinuing in 2012). The main problem with these systems is that it puts the onus of data entry on the patient, which is extremely error prone and worthless in emergency situations. In addition, use of these PHRs has not been shown to improve any leading health indicator.

As stated earlier the road to big data involves incorporating more than just patient medical records. Your health is the cumulative result of your daily habits. Monitoring those habits could help clinicians and patients suggest personalized interventions to improve long term health. Today, many people are using their smart phones and other wearable devices to monitor their activities. Currently devices record everything from daily exercise, sleep patterns, heart beat anomalies, blood sugar, and even brain function. The possibilities are ever increasing as new devices and apps come to market. According to ABI research, there will be 480 million wearable devices in use by 2018. Most of these devices come with flashy interfaces to visualize recorded data for the user, but again there is lack interoperability. There is no way to see all your collected metrics across a variety of devices. Furthermore, the data generated from these devices is not available to your traditional health care providers. Luckily a number of start-ups have sprung up to unify device data streams and make them more functioning for users and clinicians alike. One particular leader in this field is Validic, a North Carolina based startup. They offer a platform that sits between devices and the health care providers. This platform aggregates all the device information into one place making it accessible to user and physician alike (highlighted by their beautiful promotion material)


By providing an API (application programing interface) for their platform, wearable device developers are saved the trouble of making their own interface to the numerous EMRs. By building just one Validic supported interface they instantly become accessible to multiple EMRs!

But with all great technologies…there are multiple people working the same idea. HumanApi a Palo Alto based startup also offers a way for health care systems to integrate the vast volume of device generated data in a meaningful way. They also provide an API for developers and an interface for health care providers to monitor and curate patient generated data. (Also their schematic is simpler!)


Both companies could leverage their patient generated data streams to build the next generation of personalized health care solutions. In addition they will help bring devices and apps from fun gadgets to true meaningful impact, bringing us closer to the much talked about “monitored life.”

All in all we are in a promising time in healthcare. The human genome, completed just over decade ago, is just starting to give up its secrets. In that time we have learned about the transcriptome, epigenome, and microbiome which are equally important to determine the programming of the human body. Combining information from wearables (and eventually invisibles) with the knowledge gained through basic science research we will gain a more complete understanding of the human condition; and how to improve it. As a doctor and a researcher I am thrilled at the possibilities and hope I can convey my passion to you (along with a little education).

I hope you have enjoyed reading my inaugural blog article. If you have any thoughts about the article please feel free to share them in the comments or contact me. Likewise, if you have any suggested topics or interesting innovations to share please get in touch.