Matthew Engel

Minimally Invasive Delivery of Mesenchymal Stems to the Nucleus Pulposus Using an In Situ Thermoresponsive Hydrogel

In July 2009, I passed a major milestone in my graduate research in the Department of Biomedical Engineering at Stony Brook University - I passed my qualifying exam! This literally required hundreds and hundreds of hours of work, during which I read over 50 scientific publications and synthesized them to come up with an original grant proposal. In this case, my challenge was to use a tissue engineering approach to treat degenerative disc disorder. Below, I will place my statement of interest plus a copy of the grant proposal and presentation I made. I most definitely learned a tremendous amount from this process, most of which I will be keeping private and storing away for later use. But it really teaches you how to make an effective presentation and to prepare thoroughly for a talk.

In a nutshell, the project focuses on stem cell implantation technology to treat spinal chord injuries associated with aging, and could also be applied to acute injuries.

Click on individual slides to see the full image

PROJECT SUMMARY: This proposal aims to design an in situ curable hydrogel composed of PNIPAAm-PEG capable of delivering therapeutic cells and drugs to the degenerated nucleus pulposus (NP) of an intervertebral disc (IVD). The therapeutic cells will be human mesenchymal stem cells (hMSCs) differentiated into NP-like cells by exposure to hypoxic low oxygen conditions in the presence of transforming growth factor β1 (TGF- β1). The hydrogel is composed of a solution containing 10% PNIPAAm-PEG(8000) at a 1:1600 ratio of PNIPAAm:PEG which undergoes a sol-gel transition at physiological temperatures (32°C). Modifications to the PEG molecular weight or concentration can be used to alter the hydrogel stiffness or sol-gel transition temperature. These properties will allow users to prepare cell and drug loaded solutions at ambient temperatures and then inject them into the degenerated disc, at which point they solidify in situ. The hydrogel is capable of being blended with small molecule inhibitors of nitric oxide synthase (NOS). The inhibition of NOS has been shown to increase proteoglycan content which can restore disc height to the degenerated IVD.

Download copy of grant proposal here (.pdf)

Today the Atlantic is reporting in an interesting article about the regional growth of patent filings in the United States. The article segregates the distribution of high-tech industries in the US by number of patents issued, an important measure of regional economic growth and technology commercialization. The data, provided by the Martin Prosperity Institue in Toronto shows that the classic industrialized regions of the US including Pittsburgh and Detroit have fallen precipitously off the map, while unsurprisingly, regions like Silicon Valley, CA and Houston, TX show significant growth in intellectual capital. New York state saw large growth in the 1990’s but has since declined in overall patent filings. With the development of new technology commercialization programs at the university centers such as the New York State Center for Biotechnology at Stony Brook University, hopefully we will begin to see growth in terms of new patents issued and licenses granted to private industry which would indicate true commercial growth. I would be extremely interested to see the distribution of patent filings by industry such as the computer software development, electrical engineering, pharmaceuticals and biotechnology sectors.

This year I have had the distinct proviledge of attending the Rapidata 2009 Course at Brookhaven National Laboratory. Organized by Robert Sweet, Alexei Soares, and many others, Rapidata 2009 has been a tremendous learning experience focusing on the practical aspects of protein crystallography (PX). Over the last 24 hours I have met students and faculty from Harvard, MIT, Rockefeller, Providence, Purdue, Oxford, Sweden, the Netherlands, Brazil and Switzerland. It is truly a gathering of some of the best crystallographers in the world who are the globe’s leaders in cryo-cooling, structure solution, phasing, software development and beamline operations. The week long program features lectures and hands on tutorials where students can bring actual samples from their home laboratories, collect data from them and solve the structure at the NSLS. I will be working on a previous data set containing multiwavelength anomolous diffraction (MAD) data and try to solve its structure. I hope to report back from the course with more details later this week.

A streaming video can be found here on the bottom of this webpage.

The full presentation was uploaded onto the BNL website, and I have a copy of it here. Below, I will share some of the slides which I thought were most critical and relevant; as each could warrant a full discussion unto itself. One of Chu’s goals was to establish the idea that our world is changing. Many peoples are not prone to understanding these types of changes, or how they will affect society. However, it is important not to ignore them but study them and try and calculate how they will impact humanity. One may ask ‘Will these changes be beneficial or detrimental? Can we alter their course, can man control them? Are these changes to our world caused by man, or a byproduct of our society?’ Chu establishes three ‘myths’ which are commonly thought to be true, and present evidence to combat each myth. They are:

1. The wealth of a country is proportional to the energy it uses and its carbon footprint.
2. Energy efficiency and CO2 reductions are not affordable.
3. We have all the technology we need to solve the energy problem. It is only a matter of political will.

The graph above shows the development index of many nations in the world including the U.S., Japan, France, Netherlands, Germany, Israel etc. in proportion to their energy consumption. From here, we can see that many developed nations all across the world are able to maintain a high standard of living while having much lower energy consumption per person. Therefore, in America we have the potential to maintain or even raise our standard of living while lowering our energy consumption - this data shows that it can be done.

Here we see the energy consumption in the United States per person in kWh compared to the energy consumption in California per person. It is obvious, there is a drastic difference between the two. The average person in California uses much less energy than the average person in the U.S. Even while the per capita GDP in California doubled, its energy consumption remained flat. This was due to greater energy efficiency practices, that we could learn from. These practices would reduce our dependence on foreign oil and help reduce pollutin emissions.

I will post this now, but continue updating it over the weekend. Enjoy, and best wishes.

Announces $150 Billion Investment Over 10 Years in Clean and Renewable Energy Research

March 23, 2009

Today I am proud to witness history. I am proud of my country, and excited about the new direction it will be taking us. As Secretary of Energy Steven Chu made his very first visit to a national laboratory since taking office, I was lucky enough to be sitting in the audience during the presentation at BNL (Brookhaven National Laboratory). His visit was accompanied by a major announcement regarding massive new investments in funding for clean and renewable energy research and experimentation as per the American Recovery and Reinvestment Act. This will have a large impact on our economy in both the near and short term. Secretary Chu’s talk was both bright and funny, serious and sobering, uplifting and inspiring. He showed many examples of global climate change- examples where increases of just a few degrees could completely alter the natrual landscape, ruining ecosystems for many of its inhabitants. He talked about the history of the Department of Energy and of Brookhaven, and our role in the nation’s energy plan. As I sat in Berkner Hall, taking notes during the talk I was quickly becoming extremely excited and inspired. Right now I feel as if something big is coming, and that real change in this field will happen during my lifetime. Here, I share my personal notes with you from the meeting.

The American Recovery and Reinvestment Act

“Science for the 21st century”

As Representative Tim Bishop began the introductions, Secretary Chu sheepishly fixed his tie off stage. Still visible to the audience, this small gesture was enough for me to realize that yes, indeed this politician of monstrous importance was truly human, and a modest one at that. A renowned thinker, a Noble Prize winner, and importantly a scientist- Chu actually grew up on Long Island. Living in Garden City, NY from age 3-18 Secretary Chu actually admits never made it to Stony Brook University during that time- but as he acknowledged “I am here now”.

Secretary Chu speaking at Brookhaven National Laboratory

“This is an exciting time to be in science”

The Secretary described the stimulus bill as a method of moving the nation forward and putting people to work. This step moving forward “underscores the President’s wisdom”, demonstrating his understanding of the dire need for research, investment, and implementation of fundamental technologies in the energy sector. This will be accomplished by a pledge to double the budget for the Department of Energy’s (DOE) Office of Science over the next ten years. Specifically, the Office of Science will receive at least $1.2 billion thru the act. Secretary Chu’s main points were:

• $15 billion per Year for Clean and Renewable Energy Research
• Permanent Tax Credit for Cleantech Research and Experimentation
• $277 million of Competetive Grants to be awarded by the Energy Fronteir Research Center

Important details of the Act and how they affect the DOE can be found here. Jeff Sherwood of at DOE headquarters has published a concise and accurate description of the specific investments and funded projects in a press release here.

This will include $90 million to support PhD and grad students in the sciences, creating thousands of new jobs. Chu’s presentation really started to snowball now as he began describing the prestigious history of the DOE, commenting on human environmental impact and importantly- energy consumption. He begain describing the prestigious history of the Department of Energy which has funded 88 Noble Prize Winners, research at over 300 universities and 17 national laboratories.

Secretary Chu Tours the STAR Detector

It is the largest funding source of physical science in the world. He begins reminiscing about the high energy physics research days of yore, which are incredibly fascinating. He describe the work of famous physicists, many of who worked simulaneously at AT&T Bell Labs while Chu was there, on world changing projects such as the transister: the fundamental unit of every modern electrical device. The problem was that the current state of the art, vacuum tubes, would burn out after one year. With the advent of quantum mechanics, a solid state replacement known as the transister was invented. One of his more humorous remarks targeted the NSLS II, now under construction. As the former Director of Lawrence Berkley National Laboratory, Secretary Chu expressed concern when he was admiring the specs of NSLS-II, that perhaps we would provide a friendly rivalry for our west coast neighbor. Now, as Secretary of Energy, Chu must leave these competing interests aside and come to the east coast and promote our accomplishments, and he did so happily and gracefully.

Tomorrow I shall continue my report of the Secretary’s visit to BNL with more details. Thanks for reading and enjoy!

President Obama repeals ban on federal funding of embryonic stem cells - March 9, 2009

On March 9, 2009 President Barack Obama removed the ban prohibiting the use of federal tax dollars for embryonic stem cell research. Specifically, on Monday a memorandum was signed allowing the White House Office of Science and Technology Policy to begin designing a strategy for carrying out this research. The earlier ban, enacted by former President Bush prevented all federal government funding for the use and development of embryonic stem cells. During this time individual states were vying to raise capital for this work on their own via private/state joint institutes. California was the leader in this, creating a $3 billion bond to support the state universities. Unfortunately, these funds were generally witheld following the ensuing political turmoil. Developments at the local level actually point towards the probability that individual states would eventually have begun financing this research, whether or not the federal government supported it.

Bush’s federal ban on embryonic stem cell funding resulted in the use of private monies for these experiments, and drastically cut down the number of academic labs studying the system. At least 6-7 years of more rapid progress was probably lost during this time. However, it did stimulate a large body of research on the use of adult derived stem cells and new technologies for generating ES cells without destroying the embryo. Without this ban, researchers at Advanced Cell Technology may never have speant so much time attempting to isolate ES cells from living embryos using biopsies, which is does not harm the embryo and is commonly performed during preimplantation genetic diagnosis (PGD). In a nutshell, PGD allows one to geneticly test embryos for disease markers before they are implanted. This is especially useful during in vitro fertilization, in which many embryos are fertilized, screened, and then transplanted into the uterus. Those embryos which carry the disease marker are not implanted.

Many new findings were made during this time period from 2001-2009, including the discovery of stem cells in the brain and other tissues. Also, the ‘reprogramming’ of adult and menenchymal stem cells into nerves or other specialized cells will have definite long term implications for disease therapy. Will it be possible to use adult derived stem cells for regenerative medicine and treating patients? Probaby not. Was it necessary to increase the research support of ES cells if we ever hope to treat Parkinson’s disease, Alzheimer’s disease or diabetes with this technology? Definitely. With the removal of this ban, universities may once again begin receiving grants and carrying out work on these totipotent cells. Importantly, it opens the door for more clinical trials and human testing in the United States. The New York Times, the Los Angeles Times, have all been reporting on this issue. Yet very few articles have actually addressed the true ethical or scientific implications of the memorandum.

Truthfully, this decision opens up a massive can of worms regarding the ethical use of embryos and ES cells during our time. Part of the root cause of this is the fault of previous administrations which neglected to address the technological advancements and fully dissect their moral implications. Instead, what amounted to an academic moratorium on ES cell research was put into effect, while other issues such as national security, defense, and wartime tactics took precedence. Some of the critical moral and scientific questions that need to be addressed are: (1) Can ES cells be generated without destroying embryos, and of so, is this as benefical in the clinic and is it efficient? (2) Is the destruction of an embryo universally considered to be an ethical objection? For instance, one may create a cloned embryo of an existing human patient using donated eggs and a cell from that patient. The embryo can be grown in vitro and potentially used to treat his/her disease. If the embryo is killed during this process, is this objectionable? The embryo came into life purely for the purpose of saving that of another. That is more useful, and productive than what is currently allowed under existing abortion law. Abortion is considered legal (but perhaps unethical) in many cases. In some cases it is ethical, for example to save the mother’s life. Therefore, is the destruction of an embryo for saving one’s life always ethical?

Brave New World by Aldous Huxley published 1932

In reality, I do not believe we are so far away from the ‘Brave New World’ scenario. Current technologies allow one to clone thyself and simply implant said embryo into the womb. Gestation of these embryos can give rise to cloned human beings, which is currently an unethical endeavor. This is due to the unknown side effects of cloning on human beings. It is expected that cloned humans, as with other mammals such as cows, pigs, and sheep would develop age related diseases more rapidly and die prematurely. In the future, it may be possible to overcome these obstacles by using DNA from the umbilical cord, but what would be the point? In my eyes, it is imperative to set ground rules and regulations preventing these types of experiments from ever happening during our era, which may or may not have much to do with embryonic stem cell therapy. However, it must be considered as the difference between therapeutic cloning and reproductive cloning is simply the implantation of an embryo.